Pathogenic mechanisms in filarial diseases are complex and poorly understood. While examining endothelium-dependent vasodilatory responses in the in vivo canine femoral artery, we noticed that dogs with Dirofilaria immitis infection had altered vascular responsiveness. The results reported here extend our original observations on vascular reactivity in dogs with D. immitis infection (L. Kaiser, J. F. Williams, E. A. Meade, and H. V. Sparks, 1987, American Journal of Physiology 253, H1325-H1329). In noninfected dogs, acetylcholine binds to the luminal endothelial cell muscarinic receptor. This results in release of a nonprostaglandin endothelium-derived relaxing factor. The relaxing factor causes an increase in vascular smooth muscle guanylate cyclase and relaxation. However, in dogs with D. immitis infection the mechanism of relaxation to acetylcholine is different. At least two endothelium derived relaxing factors are involved: the major factor is a prostaglandin; the second factor works through vascular smooth muscle cGMP. These data suggest that adult D. immitis release pharmacologically active factors that can alter distal endothelial cell function. The notion that filarial products may alter the physiological function of endothelial cells should be considered in the pursuit of improved understanding of pathogenic mechanisms of filariasis.